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Diabetic peripheral neuropathy (DPN) is a common diabetes complication (DM). Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired. In response, a pharmacophore model based on the properties of eplarestat was generated. The specified pharmacophore model searched the NuBBEDB database of natural compounds for prospective lead candidates. To assess the drug-likeness and ADMET profile of the compounds, a series of in silico filtering procedures were applied. The compounds were then put through molecular docking and interaction analysis. In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.
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PKP1 has been crucially involved in enhancing the MYC translation leading to lung carcinogenesis via evading numerous tumour-suppressing checkpoint systems. Plakophilin 1(PKP1) is the part of armadillo and plakophilin gene families and it is a necessary component of desmosomes. Several researches reported PKP1 protein as one of the most overexpressed proteins in human lung cancer. Therefore, we have designed our research towards elucidating better plant-based compounds as drug candidates for the management of lung cancer with minimal adverse effects over other chemotherapeutic drugs such as afatinib. This study comprises forty-six flavonoids for targeting PKP1 using in silico approaches that were not used earlier as an anti-cancerous agent targeting PKP1 in lung cancer treatment. Flavonoids are plant-derived natural compounds that exhibited enormous anti-cancerous potential against several human cancers. NPACT database was used to screen potent flavonoids that have not been used to target the PKP1 protein in lung cancer. Patch Dock and CB Dock were employed to elucidate the PKP1 (1XM9) inhibitory potential of selected flavonoids. Analysis with both the docking tools has revealed that calyxins I showed maximum affinity in comparison to the standard drug, afatinib. Further PASS and BAS analyses were performed using SWISS ADME and molinspiration to investigate the pharmacokinetic profiling of potent flavonoids having significant binding energy. Visualization of complexes was done by using UCSF chimera. However, further detailed in vitro studies are needed to validate the candidature of calyxinsI for being developed as an anticancer drug for the management of lung cancer.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Afatinib , Neoplasias Pulmonares/tratamento farmacológico , Proteínas/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Placofilinas/genética , Placofilinas/metabolismoRESUMO
The hunt for potential lead/drug molecules from different resources, especially from natural resources, for possible treatment of COVID-19 is ongoing. Several compounds have already been identified, but only a few are good enough to show potential against the virus. Among the identified druggable target proteins of SARS-CoV-2, this study focuses on non-structural RNA-dependent RNA polymerase protein (RdRp), a well-known enzyme for both viral genome replication and viral mRNA synthesis, and is therefore considered to be the primary target. In this study, the virtual screening followed by an in-depth docking study of the Compounds Library found that natural compound Cyclocurcumin and Silybin B have strong interaction with RdRp and much better than the remdesivir with free binding energy and inhibition constant value as êzÅ-6.29 kcal/mol and 58.39 µMêzÅ, and êzÅ-7.93kcal/mol and 45.3 µMêzÅ, respectively. The finding indicated that the selected hits (Cyclocurcumin and Silybin B) could act as non-nucleotide anti-polymerase agents, and can be further optimized as a potential inhibitor of RdRp by benchwork experiments.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/metabolismo , Produtos Biológicos/metabolismo , COVID-19/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular/métodos , Compostos Fitoquímicos/metabolismo , SARS-CoV-2/enzimologia , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Alanina/química , Alanina/metabolismo , Antivirais/química , Produtos Biológicos/química , COVID-19/virologia , Domínio Catalítico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/química , Curcumina/análogos & derivados , Curcumina/química , Curcumina/metabolismo , Bases de Dados de Proteínas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Compostos Fitoquímicos/química , Ligação Proteica , Silibina/química , Silibina/metabolismoRESUMO
Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (Mpro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski's filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as Mpro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.
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Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Tratamento Farmacológico da COVID-19 , Receptores de Droga/metabolismo , Sítios de Ligação , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Quantitativa Estrutura-AtividadeRESUMO
Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of -7.19, -7.95, and -7.21 kcal/mol for the monomer (K-chain) and -8.05, -9.10, and -7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (-5.83 kcal/mol (monomer) and -5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome.
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Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Domínio Catalítico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Tuberculose/microbiologiaRESUMO
Diabetes mellitus is a multifactorial disease that affects both developing and developed countries and is a major public health concern. Many synthetic drugs are available in the market, which counteracts the associated pathologies. However, due to the propensity of side effects, there is an unmet need for the investigation of safe and effective drugs. This research aims to find a novel phytoconstituent having diminished action on blood glucose levels with the least side effects. Shikonin is a naturally occurring naphthoquinone dying pigment obtained by the roots of the Boraginaceae family. Besides its use as pigments, it can be used as an antimicrobial, anti-inflammatory, and anti-tumor agent. This research aimed to hypothesize the physicochemical and phytochemical properties of Shikonin's in silico interaction with protein tyrosine phosphate 1B, as well as it's in vitro studies, in order to determine its potential anti-diabetic impact. To do so, molecular docking experiments with target proteins were conducted to assess their anti-diabetic ability. Analyzing associations with corresponding amino acids revealed the significant molecular interactions between Shikonin and diabetes-related target proteins. In silico pharmacokinetics and toxicity profile of Shikonin using ADMET Descriptor, Toxicity Prediction, and Calculate Molecular Properties tools from Biovia Discovery Studio v4.5. Filter by Lipinski and Veber Rule's module from Biovia Discovery Studio v4.5 was applied to assess the drug-likeness of Shikonin. The in vitro studies exposed that Shikonin shows an inhibitory potential against the PTP1B with an IC50 value of 15.51 µM. The kinetics studies revealed that it has a competitive inhibitory effect (Ki = 7.5 M) on the enzyme system, which could be useful in the production of preventive and therapeutic agents. The findings of this research suggested that the Shikonin could be used as an anti-diabetic agent and can be used as a novel source for drug delivery.
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Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Naftoquinonas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Regulação Alostérica , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Relação Estrutura-AtividadeRESUMO
SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.
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Antivirais/farmacologia , Endorribonucleases/química , Ensaios de Triagem em Larga Escala/métodos , Proteínas não Estruturais Virais/química , Antivirais/química , Antivirais/farmacocinética , Domínio Catalítico , Endorribonucleases/metabolismo , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas não Estruturais Virais/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Lymphatic filariasis (LF) is a chronic and debilitating disease that affects people in tropical and sub-tropical areas of Asia, Africa, and Western Pacific. It is one of the leading community health problems in some of the endemic districts in India including Hardoi district of Uttar Pradesh. The disease is caused by the parasites Wuchereria bancrofti (W. bancrofti), Brugia malayi (B. malayi) and Brugia timori (B. timori), transmitted by the vector Culex, Anopheles and other mosquitoes. This cross-sectional survey study was carried out in rural areas, where its inhabitants vary in socio-economic status, from low to middle-income class. 12 villages of Hardoi district, Uttar Pradesh, India were included. The aim was to see the impact of age and gender on various clinical forms of LF and in estimating its economic and social implications. 260 LF affected people in different parts of Hardoi district were surveyed. The results revealed that the Mass Drug Administration (MDA) coverage reached more than 90%. The overall Microfilaria rate had been reduced, however the prevalence of elephantiasis increased with the progression of age and was found to be highest among people of >70 years of age, regardless of their gender.
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Filariose Linfática/epidemiologia , Filariose Linfática/prevenção & controle , Doenças Endêmicas/prevenção & controle , Administração Massiva de Medicamentos , Adolescente , Adulto , Fatores Etários , Idoso , Albendazol/uso terapêutico , Animais , Anopheles/parasitologia , Antiparasitários/uso terapêutico , Brugia Malayi/efeitos dos fármacos , Criança , Estudos Transversais , Culex/parasitologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Fatores Socioeconômicos , Wuchereria bancrofti/efeitos dos fármacosRESUMO
Knowledge of genetic variability within and among types and breeds of dromedary (Camelus dromedarius L.) can be a valuable asset in selective breeding of desirable characteristics and will shed light on their origin, dynamics of domestication, and dispersion. Variability in an 809 bp segment of the mtDNA genome was measured within and among dromedaries from eight indigenous and one exogenous breed from Ha'il in north-central Saudi Arabia. Sixteen mtDNA haplotypes were identified among 47 camels. Haplotypic diversity among breeds is high (Hd = 0.817); most of the AMOVA variance (55.05%) occurs within breeds. Phylogenetic comparison of these haplotypes with those obtained across their geographic range showed that most haplotypes were placed within the same cluster with ancient wild dromedaries and the two newly identified haplotypes in this study. The most prevalent haplotypes found in dromedaries from this area appear to be ancestral to most other dromedaries and differ from each other by only one SNP. These results support the hypothesis that the Arabian Peninsula is a hub of diversification for dromedaries.
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Camelus , DNA Mitocondrial , Variação Genética , Haplótipos , Filogenia , Animais , Camelus/genética , Camelus/classificação , Arábia Saudita , DNA Mitocondrial/genética , Polimorfismo de Nucleotídeo Único , CruzamentoRESUMO
The propagation of Ca2+ wave through gap junction in smooth muscle cell is studied as a function of electrical coupling parameter (g) modulated by Ca2+ level in the cell. The range of activation time of Ca2+ propagation with amplitude is found to increase as increase in electrical coupling parameter g, which is identified by increase in critical time of activation, T(F) as a function of g. Then identical Ca2+ oscillators are allowed to interact via electrical and diffusive coupling of Ca2+ ions diffused through gap junctions, and rate of intercellular synchronization among them is studied. The phase diagrams in (T(F) - g) and (T(F) - epsilon) parameter spaces separate oscillation death and damped oscillations regimes which correspond to deactivated and activated regimes of Ca2+ level. The effect of on T(F) is significantly very slow, however it enhances the rate of synchronization among the coupled oscillators. The increase in g comparatively slows down the rate of synchronization of the coupled oscillators as shown in the phase diagram in (epsilon - g) parameter space which separates desynchronized and synchronized regimes.
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Potenciais de Ação/fisiologia , Relógios Biológicos/fisiologia , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Modelos Neurológicos , Miócitos de Músculo Liso/fisiologia , Transmissão Sináptica/fisiologia , Animais , Simulação por Computador , HumanosRESUMO
Diabetes is a complicated multifactorial disorder in which the patient generally observes polyphagia, polydipsia, and polyuria due to uncontrolled growth in blood sugar levels. For its management, the pharmaceutical industry is working day and night to find a better drug with no or least toxicity. That's why nowadays a more focused branch is to use herbal phytoconstituents for its prevention. Shikonin is a naphthoquinone natural dye that is isolated from the plants of the Boraginaceae family and has proven its role as an anti-cancer, anti-inflammatory, and anti-gonadotrophic agent. In our previous study, we have published its anti-diabetic action by inhibiting the enzyme protein tyrosine phosphatase 1B. In this study, we were more focused on finding out the role of Shikonin and its pharmacophores by inhibiting the action of aldose reductase (AR) enzyme. The study was conducted using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies. The absorption, distribution, metabolism, excretion (ADME), and toxicity profile were also evaluated in this study. Along with all the computational biology parameters we also focused on the in vitro activity and kinetic study of inhibitory activity of Shikonin against aldose reductase.
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Diabetes Mellitus , Naftoquinonas , Aldeído Redutase/metabolismo , Diabetes Mellitus/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Acoplamento Molecular , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêuticoRESUMO
Cardiovascular disease is a well-known and widely studied disease. Epidemiological studies indicated that the mortality rate due to cardiovascular diseases increases every year. According to the WHO (world health organization) report, cardiovascular disease is one of the most prevalent non-communicable diseases in Saudi Arabia. Moreover, the Ministry of Health, Kingdom of Saudi Arabia, also reported that 42% of the non-communicable disease death is associated with cardiovascular disease in Saudi Arabia. Various reports suggest that heart disease is associated with several risk factors. Moreover, diabetes is one of the high-risk factors. Clinical result suggests a good association between diabetes and cardiovascular complications. In the present work, we focus on some of the important risk factors responsible for heart disease such as weight, blood pressure, age, and diabetes. A set questionnaire, which includes all the parameters associated with cardiovascular disease, was prepared. Data collected from the heart patient's records of different hospitals in Al-Qassim, Saudi Arabia. We applied statistical tools to analyze the data. Our results shows very interactive and significant pattern. We found significant inter-correlation between the different risk factors. In conclusion, the inter-correlation among different risk factors of heart disease is found. It is suggested that both pre and post-heart patients should be more concern about these risk factors. Moreover, this study can be used for further research, and, will increase people awareness regarding their healthy choice.
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Methicillin resistant Staphylococcus aureus infections impose a huge risk to public health in healthcare and community settings worldwide. Therefore, it is of interest to document data on the anti-biogramas and genotypes of isolates from Saudi Arabia. We assessed the antimicrobial susceptibility, determined spa (protein A gene) and analyzed multilocus MLST genotypes, and detected PVL gene in these isolates. We collected 28 clinical MRSA isolates, cultured and determined the minimum inhibitory concentrations of 17 antimicrobial agents using Vitek2 system (BioMerieux, USA) from 3 hospitals in Saudi Arabia during the year 2012. Polymorphic region of the spa and seven housekeeping genes were amplified and sequenced. BioNumerics v.5.1 (Applied Maths) was used for spa typing and MLST. Samples were screened for the presence of PVL and mecA genes using polymerase chain reaction (PCR). Analysis shows that all isolates were susceptible to chloramphenicol, rifampicin, nitrofurantoin, teicoplanin, daptomycin and vancomycin. The T4573/ST22 strains are found to be prevalent in the Saudi Arabia (N=6, 21%). We further noted that three isolates (t363/ST240 strain) were resistant to eight antimicrobial agents. Most of t4573/ST22 strains were PVL positive, resistant to ciprofloxacin and linked to HA-MRSA infections. We document data for the presence of emerging multi drug resistant S. aureus strains carrying the PVL gene circulating within hospitals. This highlights the urgent need for continuous active surveillance and implementation of prevention measures.
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BACKGROUND: Understanding of cervical cancer severity is still an important health issue across the world, especially for developing countries. Cancer or abnormal growth of the cell is one of the major health problems of the world. There are about two hundred types of malignancies reported till date. An updated statistic of all the main types of cancer and pathophysiology of cervical cancer is a significant need for designing the future treatment strategy. OBJECTIVE: In this review, a brief update on cancer, its causes and different types has been discussed along with updated statistics of patient's mortality. A brief overview of cervical cancer and its pathophysiology has been discussed with special emphasis on its causative agent, human papilloma virus (HPV). A brief introduction and update on genetics, molecular pathogenesis and prevalence of HPV and its role in cervical cancer have been added. CONCLUSION: This review delivered an updated status of cervical cancer and provide novel therapeutic approaches for targeting HPV. The detailed molecular and genomic information of the HPV help the researchers to develop more effective and efficacious therapeutic strategies and preventive vaccines that will significantly contribute to the control and anticipation of cervical cancer. Ultimately this may open new vistas to get rid of this deadly disease and may offer significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer in the affected nations.
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Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/etiologia , Feminino , Genes Supressores de Tumor , Genoma Viral , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/transmissão , Neoplasias do Colo do Útero/epidemiologiaRESUMO
The nuclear matrix associated protein SMAR1 is sensitive to p53 and acts as a stress inducer as well as a regulator in the p53 regulatory network. Depending on the amount of stress SMAR1 stimulates, it can drive the p53 dynamics in the system to various dynamical states which correspond to various cellular states. The behavior of p53 in these dynamical states is found to be multifractal, due to the mostly long range correlations and large scale fluctuations imparted by stress. This fractal behavior is exhibited in the topological properties of the networks constructed from these dynamical states, and is a signature of self-organization to optimize information flow in the dynamics. The assortativity found in these networks is due to perturbation induced by stress, and indicates that the hubs in the time series play a significant role in stress management. SMAR1 can also regulate apoptosis in the presence of HDAC1, depending on the stress induced by it.
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Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Algoritmos , Proteínas de Transporte , Dano ao DNA , Fractais , Histona Desacetilase 1/metabolismo , Humanos , Modelos Biológicos , Ligação Proteica , Proteína Supressora de Tumor p53/metabolismo , Fluxo de TrabalhoRESUMO
We study transition of the temporal behaviours of p53 and MDM2 in a stress p53-MDM2-NO regulatory network induced by a bioactive molecule NO (Nitric Oxide). We further study synchronization among a group of identical stress systems arranged in a 3D array with nearest neighbour diffusive coupling. The role of NO and the effect of noise are investigated. In the single system study, we found three distinct types of temporal behaviour of p53, namely oscillation death, damped oscillation and sustained oscillation, depending on the amount of stress induced by NO, indicating how p53 responds to incoming stress. The correlation among coupled systems increases as the value of the coupling constant (ϵ) is increased (γ increases) and becomes constant after a certain value of ϵ. The permutation entropy spectra H(ϵ) for p53 and MDM2 as a function of ϵ are found to be different due to direct and indirect interaction of NO with respective proteins. We find γ versus ϵ for p53 and MDM2 to be similar in a deterministic approach but different in a stochastic approach, and the separation between γ of the respective proteins as a function of ϵ decreases as system size increases. The role of NO is found to be two-fold: stress induced by NO is prominent at small and large values of ϵ but synchrony induced by it dominates in the moderate range of ϵ. Excess stress induces apoptosis.
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Modelos Biológicos , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Entropia , HumanosRESUMO
We study the regulating mechanism of p53 on the properties of cell cycle dynamics in the light of the proposed model of interacting p53 and cell cycle networks via p53. Irradiation (IR) introduce to p53 compel p53 dynamics to suffer different phases, namely oscillating and oscillation death (stabilized) phases. The IR induced p53 dynamics undergo collapse of oscillation with collapse time Δt which depends on IR strength. The stress p53 via IR drive cell cycle molecular species MPF and cyclin dynamics to different states, namely, oscillation death, oscillations of periods, chaotic and sustain oscillation in their bifurcation diagram. We predict that there could be a critical Δtc induced by p53 via IRc, where, if ΔtãΔtc the cell cycle may come back to normal state, otherwise it will go to cell cycle arrest (apoptosis).
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Ciclo Celular/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Ciclo Celular/efeitos da radiação , Ciclinas/metabolismo , Fator Promotor de Maturação/metabolismo , Modelos Biológicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Radiação IonizanteRESUMO
We present the mechanism of interaction of Wnt network module, which is responsible for periodic somitogenesis, with p53 regulatory network, which is one of the main regulators of various cellular functions, and switching of various oscillating states by investigating p53-Wnt model. The variation in Nutlin concentration in p53 regulating network drives the Wnt network module to different states, stabilized, damped and sustain oscillation states, and even to cycle arrest. Similarly, the change in Axin2 concentration in Wnt could able to modulate the p53 dynamics at these states. We then solve the set of coupled ordinary differential equations of the model using quasi steady state approximation. We, further, demonstrate the change of p53 and GSK3 interaction rate, due to hypothetical catalytic reaction or external stimuli, can able to regulate the dynamics of the two network modules, and even can control their dynamics to protect the system from cycle arrest (apoptosis).
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Redes Reguladoras de Genes , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt , Apoptose , Proteína Axina/metabolismo , Redes Reguladoras de Genes/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Imidazóis/metabolismo , Modelos Biológicos , Piperazinas/metabolismo , Proteína Supressora de Tumor p53/genética , Via de Sinalização Wnt/genéticaRESUMO
Various studies reported that, nowadays, our lifestyle is a major source of many diseases. The present aim of this paper is to cross-sectional study about the awareness of a group of people regarding their lifestyle, associated disease, and awareness of government health care facilities. We carried our study in Ha’il, Kingdom of Saudi Arabia (KSA). For the present study, we consider 292 objects from Ha’il, Kingdom of Saudi Arabia, with various exclusion criteria such as suffering from any form of mental illness, suffering from any form of physical disabilities, suffering from any chronic illness that require regular prescriptions, no formal education, age below 25 years and above 50 years. The questionnaires were distributed among the participants. Next, we analyzed the data using various statistical measures. Our analysis showed that awareness among the group of people regarding their lifestyle, associated disease, and awareness of government health care facilities is not satisfactory. They have very few training in immunology. They have some awareness about government health care policies. Our study concludes that there is an urgent need for people’s awareness by establishing various health camps as well as various media. Our study will help the government policymaker to design effective policy regarding better health care facilities for the public especially in Ha’il, Kingdom of Saudi Arabia. Moreover, further study is required for finding the missing link between people’s awareness and available public health care facilities.
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The integration of calcium and a p53-Mdm2 oscillator model is studied using a deterministic as well as a stochastic approach, to investigate the impact of a calcium wave on single cell dynamics and on the inter-oscillator interaction. The high dose of calcium in the system activates the nitric oxide synthase, synthesizing nitric oxide which then downregulates Mdm2 and influences drastically the p53-Mdm2 network regulation, lifting the system from a normal to a stressed state. The increase in calcium level switches the system to different states, as identified by the different behaviours of the p53 temporal dynamics, i.e. oscillation death to sustain the oscillation state via a mixed state of dampened and oscillation death states. Further increase of the calcium dose in the system switches the system from sustained to oscillation death state again, while an excess of calcium shifts the cell to an apoptotic state. Another important property of the calcium ion is its ability to behave as a synchronizing agent among the interacting systems. The time evolution of the p53 dynamics of the two diffusively coupled systems at stress condition via Ca(2+) shows synchronization between the two systems. The noise contained in the system interestingly helps the system to maintain its stabilized state (normal condition). However, noise has the tendency to destruct the synchronization effect, which means that it tries to restrict the system from external signals to maintain its normal condition. However, at the stress condition, the synchronization rate is found to be faster.